a. Field of the Invention
The present invention relates generally to methods for the treatment of neurological conditions, and, more particularly, to a method for alleviating/controlling symptoms associated with neurodegeneration and similar conditions stemming from multiple sclerosis, autoimmune diseases, aging, and other causes, by administration of a compound effective to increase synaptic methylation of histamine without reliance on endogenous histamine N-methyltransferase (HMT) activity or exogenous administration of HMT.
b. Related Art
Neurodegenerative conditions, which include diseases of autoimmunity, strike an increasingly large number of individuals each year, and for many of these conditions conventional treatments offer little in the way of true relief. A particularly widespread and well-known example is multiple sclerosis (referred to from time-to-time hereinafter as “MS”).
In some instances, the neurodegenerative conditions are more or less specifically associated with a particular disease, such as multiple sclerosis, while in other instances the conditions are associated more generally with aging or some other condition or process of the body, such as a genetic disorder or an autoimmune disease, fibromyalgia, for example. As a group, however, these conditions are characterized by weakness and impaired physical functions, and, sometimes, impaired mental functions as well. Debilitation is often progressive, and, as stated, conventional treatments and therapies have been limited in their success.
For purposes of illustration, the invention will be described below largely in the context of multiple sclerosis, which is a condition to which the invention has particular applicability; however, it will be understood that the present invention is applicable to a range of neurodegenerative conditions such as those noted above, including autoimmune diseases, fibromyalgia and others, and therefore is not limited in scope to the treatment of multiple sclerosis alone.
As is known, multiple sclerosis is a chronic degenerative disease of the central nervous system, characterized by demyelination of the nerve axons. Symptoms include varying degrees of fatigue, numbness, tremors/muscle spasms and paralysis, coupled with a heightened susceptibility to heat and other environmental stressors. Currently, approximately 4,000,000 people worldwide have been diagnosed as having multiple sclerosis. Onset of the disease usually occurs between 20 and 40 years of age.
It is recognized that MS occurs in at least two general types, i.e. “remissive-relapsive”, in which acute exacerbations are separated by periods of partial recovery, and “chronic-progressive”, in which the symptoms continue generally unrelieved and there is a progressive deterioration of the patient's condition that may eventually result in total debilitation.
Efforts at treatment of MS have heretofore concentrated almost entirely on the body's autoimmune response system. The prevailing theory has been that some agent causes the myelin sheath to be attacked by the immune system, resulting in destruction of the myelin and creation of lesions. It is also believed that certain viruses may play a role in causing or precipitating MS: In particular, the measles virus may be involved in the disease, in that studies have not only found that people suffering from MS almost invariably possess the measles antigen, but also that MS patients generally have higher than normal levels of measles antibodies in their serum and cerebrospinal fluid. One theory has been that the measles or other virus triggers the T-cells to attack and destroy the myelin sheath.
Proceeding on the theory that MS is the result of an autoimmune response triggered by measles or another virus, most conventional treatment techniques have involved the use of Betaseron, Avonex, Rebif and/or other antiviral substances, generally referred to collectively as “Interferon”. The intended purpose of these materials is to impede the RNA-DNA transcription process in the T-cells, which is believed to be triggered by the virus attacking the myelin. While interferon has demonstrated some positive results when treating remissive-relapsive type MS, it has proven almost entirely ineffective against the chronic-progressive type.
Another treatment method, that has yielded modest success in alleviating the symptoms associated with multiple sclerosis, is the transdermal administration of an H2 agonist such as histamine diphosphate, together with a phosphodiesterase inhibitor such as caffeine citrate to stimulate production of cyclic AMP at a level which is sufficient to maintain myelin against undergoing self-degeneration. This treatment is described in U.S. Pat. No. 6,277,402, the inventor therein being the same as in the present matter. A related treatment, again by the same inventor described in U.S. Publication No. 20030113309, involves administering monoamine oxidase-A or monoamine oxidase-A agonists to increase the neuronal metabolism of histamine to a histamine H2 agonist.
As is described in the above references, histamine in the neurons is metabolized by histamine N-methyltransferase (HMT) into tele-methylhistamine (N-tau-methylhistamine). Tele-methylhistamine is then metabolized by monoamine oxidase-A into 4-methylhistamine (histamine methylimidazoleacetaldehyde) which is an H2 agonist. HMT is considered to be the rate-limiting enzyme in this metabolic pathway of metabolizing histamine into histamine methylimidazoleacetaldehyde, in that the histamine must be methylated before the monoamine oxidase-A can metabolize it into the H2 agonist. Research shows that HMT level of activity is regulated by inheritance (Preuss et al, 1998). Thus, the degree of effectiveness of the treatment disclosed in U.S. Pat. No. 6,277,402 could be dependent on the endogenous level of activity of HMT that in turn may be determined by inheritance.
Accordingly, there is a need for a treatment for neurodegenerative conditions such as those described above, in which neuronal metabolism of histamine to a histamine H2 agonist is enhanced without relying on the patient's potentially impaired endogenous HMT activity.